TY - JOUR
T1 - Development of a cancer cells self-activating and miR-125a-5p expressing poly-pharmacological nanodrug for cancer treatment
AU - Chang, Yung Chieh
AU - Shieh, Min Chieh
AU - Chang, Yen Hsuan
AU - Huang, Wei Lun
AU - Su, Wu Chou
AU - Cheng, Fong Yu
AU - Cheung, Chun Hei Antonio
N1 - Funding Information:
The present study was supported by the Ministry of Science and Technology of Taiwan (grant nos. 109‑2320‑B‑006‑031 and 110‑2320‑B‑006‑047‑MY3) and the ditmanson Medical Foundation chia‑Yi christian Hospital of Taiwan (grant no. cYc109006).
Publisher Copyright:
© 2022 Spandidos Publications. All rights reserved.
PY - 2022/8
Y1 - 2022/8
N2 - Cancer cells can acquire resistance to targeted therapeutic agents when the designated targets or their down- stream signaling molecules develop protein conformational or activity changes. There is an increasing interest in developing poly-pharmacologic anticancer agents to target multiple oncoproteins or signaling pathways in cancer cells. The microRNA 125a-5p (miR-125a-5p) is a tumor suppressor, and its expression has frequently been downregulated in tumors. By contrast, the anti-apoptotic molecule BIRC5/SURVIVIN is highly expressed in tumors but not in the differentiated normal tissues. In the present study, the development of a BIRC5 gene promoter-driven, miR-125a-5p expressing, poly-L-lysine-conjugated magnetite iron poly-pharmacologic nanodrug (pL-MNP-pSur-125a) was reported. The cancer cells self-activating property and the anticancer effects of this nanodrug were examined in both the multidrug efflux protein ABCB1/MDR1-expressing/-non-expressing cancer cells invitroandinvivo.ItwasdemonstratedthatpL-MNP-pSur-125a decreased the expression of ERBB2/HER2, HDAC5, BIRC5, and SP1, which are hot therapeutic targets for cancer in vitro. Notably, pL-MNP-pSur-125a also downregulated the expres- sion of TDO2 in the human KB cervical carcinoma cells. PL-MNP-pSur-125a decreased the viability of various BIRC5-expressing cancer cells, regardless of the tissue origin or the expression of ABCB1, but not of the human BIRC5-non-expressing HMEC-1 endothelial cells. In vivo, pL-MNP-pSur-125a exhibited potent antitumor growth effects, but without inducing liver toxicity, in various zebrafish human-ABCB1-expressing and ABCB1-non-expressing tumor xenograft models. In conclusion, pL-MNP-pSur-125a is an easy-to-prepare and a promising poly-pharmacological anticancer nanodrug that has the potential to manage numerous malignancies, particularly for patients with BIRC5/ABCB1-related drug resistance after prolonged chemotherapeutic treatments.
AB - Cancer cells can acquire resistance to targeted therapeutic agents when the designated targets or their down- stream signaling molecules develop protein conformational or activity changes. There is an increasing interest in developing poly-pharmacologic anticancer agents to target multiple oncoproteins or signaling pathways in cancer cells. The microRNA 125a-5p (miR-125a-5p) is a tumor suppressor, and its expression has frequently been downregulated in tumors. By contrast, the anti-apoptotic molecule BIRC5/SURVIVIN is highly expressed in tumors but not in the differentiated normal tissues. In the present study, the development of a BIRC5 gene promoter-driven, miR-125a-5p expressing, poly-L-lysine-conjugated magnetite iron poly-pharmacologic nanodrug (pL-MNP-pSur-125a) was reported. The cancer cells self-activating property and the anticancer effects of this nanodrug were examined in both the multidrug efflux protein ABCB1/MDR1-expressing/-non-expressing cancer cells invitroandinvivo.ItwasdemonstratedthatpL-MNP-pSur-125a decreased the expression of ERBB2/HER2, HDAC5, BIRC5, and SP1, which are hot therapeutic targets for cancer in vitro. Notably, pL-MNP-pSur-125a also downregulated the expres- sion of TDO2 in the human KB cervical carcinoma cells. PL-MNP-pSur-125a decreased the viability of various BIRC5-expressing cancer cells, regardless of the tissue origin or the expression of ABCB1, but not of the human BIRC5-non-expressing HMEC-1 endothelial cells. In vivo, pL-MNP-pSur-125a exhibited potent antitumor growth effects, but without inducing liver toxicity, in various zebrafish human-ABCB1-expressing and ABCB1-non-expressing tumor xenograft models. In conclusion, pL-MNP-pSur-125a is an easy-to-prepare and a promising poly-pharmacological anticancer nanodrug that has the potential to manage numerous malignancies, particularly for patients with BIRC5/ABCB1-related drug resistance after prolonged chemotherapeutic treatments.
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U2 - 10.3892/IJMM.2022.5158
DO - 10.3892/IJMM.2022.5158
M3 - Article
C2 - 35703361
AN - SCOPUS:85132050385
SN - 1107-3756
VL - 50
JO - International journal of molecular medicine
JF - International journal of molecular medicine
IS - 2
M1 - 102
ER -